title: Evaluation of chlorinated benz[a]anthracene on hepatic toxicity in rats and mutagenic activity in Salmonella typhimurium.
abstract: Chlorinated benz[a]anthracenes (Cl-BaA) are halogenated aromatic compounds (typified by dioxins) found in the environment at relatively high concentrations. Fischer 344 rats were intragastrically administered 0, 1, or 10 mg of Cl-BaA or its parent compound benz[a]anthracene (BaA) per kg of body weight for 14 consecutive days. Both chemicals at 10 mg/kg/day inhibited the gain in body weight, and consequent increase in relative liver weight. Hepatic gene expression of cytochrome P450 (CYP) 1A1, 1A2, and 1B1 was significantly stimulated by administration of BaA (10 mg/kg/day) compared with the control. After administration of Cl-BaA, only the CYP1A2 gene was significantly induced, even at the lower dosage; CYP1A1 and 1B1 mRNA levels remained unchanged in Cl-BaA-treated rats compared with controls. To elucidate the role of such Cl-BaA exposure and induced CYPs at toxicity onset, we investigated the mutagenicity of BaA and Cl-BaA using Salmonella typhimurium TA98 and TA100. BaA and Cl-BaA at 10 μg/plate produced positive results in both strains in the presence of rat S-9. Incubation of Cl-BaA with recombinant rat CYP1A2 produced a significantly higher number of revertant colonies in TA98 and TA100 than in controls, but no such change was observed for BaA. In conclusion, BaA changes its own physiological and toxicological actions by its chlorination; (1) daily exposure to Cl-BaA selectively induces hepatic CYP1A2 in rats and (2) Cl-BaA induces frameshift mutations in the presence of CYP1A2, although BaA does not exert mutagenicity. This indicates that CYP1A2 may metabolize Cl-BaA to active forms.
authors.affiliation: Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kido
authors.forename: H
authors.initials: H
authors.lastname: Sakakibara
authors.forename: T
authors.initials: T
authors.lastname: Ohura
authors.forename: K S
authors.initials: KS
authors.lastname: Guruge
authors.forename: M
authors.initials: M
authors.lastname: Kojima
authors.forename: J
authors.initials: J
authors.lastname: Hasegawa
authors.forename: T
authors.initials: T
authors.lastname: Iwamura
authors.forename: N
authors.initials: N
authors.lastname: Yamanaka
authors.forename: S
authors.initials: S
authors.lastname: Masuda
authors.forename: M
authors.initials: M
authors.lastname: Sakaguchi
authors.forename: T
authors.initials: T
authors.lastname: Amagai
authors.forename: K
authors.initials: K
authors.lastname: Shimoi
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D003580:Cytochromes / Q000378:metabolism; D016368:Frameshift Mutation; D005786:Gene Expression Regulation / Q000187:drug effects; D054879:Halogenation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001551:Benz(a)Anthracenes; D003580:Cytochromes; D009153:Mutagens; C030935:benz(a)anthracene; D001189:Aryl Hydrocarbon Hydroxylases; C017170:Cyp1a2 protein, rat; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1